{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ITIH3 is a member of the inter‑α‑trypsin inhibitor (ITI) heavy‐chain gene family that is involved in the stabilization of the extracellular matrix through its ability to bind hyaluronan. Several large‐scale genetic studies have repeatedly implicated variants within the NEK4–ITIH1–ITIH3–ITIH4 gene cluster in psychiatric disorders such as bipolar disorder, schizophrenia, and in the manifestation of suicidal behavior, suggesting that ITIH3 may contribute to neurodevelopment, neuroplasticity, and neurosignaling processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In oncology, studies of the ITI gene family have shown frequent downregulation in solid tumors, with evidence that expression of ITIH3 and related heavy chains can inhibit metastasis, supporting their role as putative tumor suppressor genes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In the cardiovascular field, a variant enhancing ITIH3 transcription has been associated with myocardial infarction, with ITIH3 protein detected in vascular smooth muscle cells and macrophages within atherosclerotic lesions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, recent work has identified cis‐regulatory effects of ITIH3 polymorphisms—linking them to altered expression of nearby genes—that may influence brain extracellular matrix composition and thereby contribute to the risk of neurodevelopmental disorders such as autism spectrum disorder."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": " Together, these findings highlight the pleiotropic functions of ITIH3 in modulating extracellular matrix stability and signaling in both peripheral tissues and the central nervous system, with diverse impacts on cancer progression, cardiovascular pathology, and psychiatric as well as neurodevelopmental disease susceptibility.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Unknown Authors "}, {"type": "b", "children": [{"type": "t", "text": "Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.943"}], "href": "https://doi.org/10.1038/ng.943"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21926972"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21926972"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Laura J Scott, Pierandrea Muglia, Xiangyang Q Kong, et al. 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